Avelumab treatment in Italian patients with metastatic Merkel cell carcinoma: experience from an expanded access program

Background The incidence of Merkel cell carcinoma (MCC), a rare form of skin cancer with a poor prognosis, has increased in Italy in recent decades. Avelumab, an anti-programmed death ligand 1 monoclonal antibody, is approved for the treatment of metastatic MCC (mMCC) based on the results of the phase 2 JAVELIN Merkel 200 trial. The global avelumab expanded access program (EAP) was designed to provide compassionate use of avelumab prior to approval for patients with mMCC who had limited treatment options. We report findings from a subgroup of Italian patients enrolled in the avelumab EAP. Methods Eligible patients had mMCC and progressive disease following ≥ 1 prior line of chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received avelumab 10 mg/kg intravenously every 2 weeks. Treating physicians were provided with an initial 3-month supply of avelumab; resupply was permitted if the patient achieved a complete response, partial response, stable disease, or other clinical benefit per physician assessment. Safety and efficacy data for the EAP were reported at the treating physician’s discretion. Results Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy, and 102 were approved. All but 1 of the approved patients had received ≥ 1 prior line of therapy. At data cutoff (March 22, 2019), 95 patients had been supplied with avelumab and response data were available for 55 patients. The objective response rate in response-evaluable patients was 29.1%, including 6 patients (10.9%) who achieved a complete response and 10 patients (18.2%) who achieved a partial response; in the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. The median duration of treatment in responding patients was 9.7 months (range, 3.5–41.7 months). The most frequently reported treatment-related adverse events were infusion-related reaction (single preferred term; n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]). Conclusions Results from Italian patients enrolled in the avelumab EAP are consistent with the findings of the JAVELIN Merkel 200 trial and confirm the efficacy and safety of avelumab treatment in this population.


Introduction
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer [1]. Compared with other skin cancers, particularly melanoma, MCC is rarer and is associated with a worse prognosis; the 10-year overall survival rate for

Open Access
Journal of Translational Medicine *Correspondence: paolo.ascierto@gmail.com 15 Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy Full list of author information is available at the end of the article Page 2 of 11 Grignani et al. J Transl Med (2021) 19:70 MCC is 18% vs. 61% for melanoma [2]. Risk factors for MCC include UV radiation exposure, advanced age, and a weakened immune system [1]. Approximately 80% of MCC cases are associated with clonal integration of the Merkel cell polyomavirus (MCPyV) [3]. The incidence of MCC has increased in Europe in recent decades, with Italy among the countries with the highest increase in MCC among men [4]. MCC can grow and metastasize quickly, and 6% to 8% of patients have distant metastatic disease at diagnosis [5][6][7]. Patients with metastatic MCC (mMCC) have limited treatment options and a poor prognosis; median survival duration with chemotherapy is approximately 10 months [1,8]. European guidelines, last published in 2015, state that apart from surgical removal of isolated metastases, there is no established curative treatment for mMCC [9].
Immune checkpoint inhibitors that block the interaction between programmed cell death protein 1 and its ligand, PD-L1, have received regulatory approval for the treatment of patients with mMCC [1]. In particular, avelumab became the first approved treatment for patients with mMCC in 2017 based on results from JAVELIN Merkel 200, a phase 2, single-arm trial (NCT02155647) [10]. After 3 years of follow-up from part A of the trial, which enrolled 88 patients with progressive disease (PD) who had received prior chemotherapy, the objective response rate (ORR) was 33.0% (95% CI 23.3-43.8%), including complete response (CR) in 11.4% [11]. After ≥ 15 months of follow-up in part B, in which 116 patients with mMCC and no prior systemic treatment for metastatic disease were treated with avelumab, 30.2% of patients had a response lasting ≥ 6 months (durable response rate), and the ORR was 39.7% (95% CI 30.7-49.2%), including CR in 16.4% [12]. In both parts A and B of the trial, responses were seen irrespective of PD-L1 or MCPyV status; however, numerically higher ORRs were reported in patients with PD-L1+ vs.  [11,12]. Avelumab has subsequently been approved in various countries worldwide for the treatment of mMCC, including in Europe [13].
For patients with no comparable or satisfactory treatment options, expanded access programs (EAPs), also called "compassionate use programs, " allow access to investigational drugs, biologics, and medical devices outside of a clinical trial [14]. The avelumab EAP was an ad hoc program designed to provide compassionate use of avelumab to patients with mMCC with limited treatment options, and participation was permitted on a patient-by-patient basis. Overall results from the global population have been reported previously [15]. This manuscript reports data from a large subgroup of patients enrolled in Italy.

Methods
To be eligible for participation in the avelumab EAP, patients were required to be ineligible for participation in any ongoing clinical trial for advanced MCC, have an Eastern Cooperative Oncology Group performance status of 0 to 3, and have measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients were also required to have either PD following ≥ 1 prior line of chemotherapy or to be ineligible to receive chemotherapy in the metastatic setting. Patient selection was not based on tumor PD-L1 expression or MCPyV status. Eligibility criteria permitted entry to the EAP for patients with treated brain metastases (without steroid use) that were not progressing or patients who were potentially immunocompromised, evaluated on a case-by-case basis; data for all immunocompromised patients enrolled in the EAP were summarized in a previous report [15].
Treating physicians were provided with a 3-month supply of avelumab, which was administered to patients at a dose of 10 mg/kg by 1-h intravenous infusion every 2 weeks. Patients received avelumab until confirmed PD, unacceptable toxicity, or other criteria for withdrawal occurred; continuation of avelumab beyond radiological PD was permitted on a case-by-case basis in the absence of significant clinical deterioration and based on physician assessment of potential clinical benefit. Patients also received premedication with antihistamine and acetaminophen to mitigate infusion-related reactions, consistent with the summary of product characteristics for avelumab [13]. Resupply of avelumab was allowed for patients with a CR, partial response, or stable disease according to RECIST 1.1 or other clinical benefit, assessed by the treating physician. Physician assessments included best overall response according to RECIST 1.1, duration of treatment for patients with response, safety, and tolerability, and data were collected prospectively. Data were provided at the treating physician's discretion, and confirmation that supplied avelumab was administered to patients was not required. All adverse events (AEs), including nonserious and serious AEs, were reported by treating physicians to a global safety database (Merck KGaA, Darmstadt, Germany Global Patient Safety), to the local health unit, and to the ethics committee at the time of resupply, progression, or death. Infusion-related reactions were defined according to a prespecified list of Medical Dictionary for Regulatory Activities terms and managed per established guidance for avelumab [13]. Immune-related AEs were identified by medical review. An online portal to process EAP requests and collate responses was implemented in May 2017.

Results
Between April 1, 2016, and September 14, 2018, 109 requests for avelumab were received from Italy. A total of 102 were approved, 2 were withdrawn before approval; additionally, 7 requests were withdrawn after approval but before supply and 5 patients did not initiate avelumab treatment. Among approved patients, the median age was 70.6 years (range, 41.0-92.0 years), and all but 1 approved patient (n = 101) were approved to receive avelumab as second-line or later treatment (i.e., had received prior chemotherapy; 1 patient was approved to receive first-line avelumab treatment; Table 1). The data cutoff was March 22, 2019.
Of 95 patients who received a supply of avelumab, response data were available for 55 patients (57.9%). In these 55 response-evaluable patients, the ORR was 29.1%, including CR in 6 (10.9%) and partial response in 10 (18.2%); 17 patients (30.9%) had stable disease as best overall response ( Table 2). As a proportion of the total population supplied with avelumab (n = 95), the proportion who had an objective response was 16.8%. Images of tumor changes in avelumab-treated patients are shown in Figs. 1, 2, 3, 4, 5 and 6. Duration of avelumab treatment (or duration that drug was supplied) was assessed as an alternative measure of duration of clinical benefit because resupply required documentation of clinical benefit by the treating physician. At data cutoff, the median treatment duration was 9.7 months (range, 3.5-41.7 months). Physician-reported safety data are summarized in Table 3. The most frequently reported treatmentrelated AEs (TRAEs) were infusion-related reaction (single preferred term, n = 3 [3.2%]) and pyrexia (n = 2 [2.1%]). One immune-related AE was reported (myasthenia gravis [1.1%]). Safety data were reported at the treating physician's discretion at the time of resupply, and many patients had no evaluable data beyond the 3-month supply; therefore, safety events were likely underreported.
Patients who achieved a CR with avelumab (n = 6) were investigated in detail, including additional follow-up beyond the cutoff date for the whole cohort (last follow-up in patients with CR, April to July 2020) ( Table 4). Patients were aged 68 to 80 years, all were male, Eastern Cooperative Oncology Group performance status was 0 or 1, and 2 patients had diabetes mellitus as a comorbidity. All patients had PD after prior chemotherapy for mMCC. Time from start of treatment to CR ranged from 1.5 to 22 months, including confirmation of metabolic CR in 2 patients. After achieving a CR with avelumab, no patient required additional local or systemic anticancer therapy, and no patient developed new lesions. TRAEs among the 6 patients were grade 1/2 only (n = 4), resolved with acetaminophen (n = 1), or did not require treatment (n = 2).

Discussion
The avelumab MCC EAP is the largest and only EAP ever opened for patients with this rare disease, enabling access to avelumab for patients with limited treatment options. The population of Italian patients reported included some patients who would not have been eligible for the pivotal JAVELIN Merkel 200 trial, including approximately 5% with an Eastern Cooperative Oncology Group performance status of 2 or 3. In addition, as reported previously for the overall global population [15], patients who were potentially immunocompromised were also eligible based on case-by-case assessment, although baseline comorbidities were not analyzed in detail for the Italian population. Data for PD-L1 expression and MCPyV status were not collected. All but 1 patient had received ≥ 1 prior line of chemotherapy before starting avelumab. The ORR in response-evaluable patients was similar to that reported in part A of the JAVELIN Merkel 200 trial, which enrolled only patients who had received ≥ 1 prior line of chemotherapy (29.1% vs. 33.0%, respectively) [11]. However, 40 patients were not evaluable for response because data were not available; unlike a clinical trial, data were submitted at the treating physician's discretion and physicians often did not submit response data (administration of supplied avelumab to patients was also not confirmed). The ORR calculated using the denominator of the total population of Italian patients supplied with avelumab was 16.8%; therefore, the "true" ORR in this population may lie within the range of 16.8% to 29.1%. The most frequently reported TRAEs were infusion-related reaction and pyrexia, and no new safety signals were identified compared with previous studies.
Data collected in this EAP have various limitations compared with data obtained in a clinical trial. Safety and efficacy data for the EAP were reported at the treating physician's discretion and are therefore potentially underreported. In this EAP population, median duration of treatment, which was assessed as an alternative measure of duration of clinical benefit, was 9.7 months, although it also likely represents an underestimate due to the nature of this EAP. In part A of JAVELIN Merkel 200, median progression-free survival was 2.7 months and median duration of response was 40.5 months [10,11]. Positron emission tomography (PET), which captures metabolic changes in tumors by measuring fluorodeoxyglucose uptake, is increasingly being used to evaluate response to cancer treatment [16]. Metabolic changes due to malignancy or inflammation are generally detected earlier than the tumor structural changes that are captured by radiological imaging techniques, such as computed tomography [16,17]. Studies in different tumor types have shown that a reduction in fluorodeoxyglucose uptake is associated with subsequent clinical and radiological responses to immunotherapy [17,18]. Furthermore, complete metabolic tumor responses documented by PET have been shown to predict early response with immune checkpoint inhibitor treatment [19,20] and may predict long-term benefit. In this EAP, 2 of the 6 patients with CR had confirmed metabolic CR by PET scan (documented in October 2017 and March 2018) and remained progression free at last follow-up (April 2020 and May 2020, respectively).

Conclusions
The efficacy and safety of avelumab seen in an Italian real-world setting, including some patients who were ineligible for chemotherapy or clinical trial participation, support the findings of the JAVELIN Merkel 200 clinical trial and confirm avelumab as an active treatment option in patients with mMCC.